Public Health Consequences of E-Cigarettes (2018) / Chapter Skim
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5 Toxicology of E-Cigarette Constituents
5 Toxicology of E-Cigarette Constituents
Pages 155-216
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From page 155... ...
Most reviewed studies have evaluated nicotine and impurities in the liquids such as TSNAs and nicotine-related impurities, while other studies have focused on identifying potentially harmful chemicals in the aerosol, such as carbonyl compounds, VOCs, TSNAs, metals, and silicates. Various chemical substances and ultrafine particles known to be toxic, carcinogenic, and/or to cause respiratory and cardiac disease have been identified in e-cigarette aerosols, cartridges, 155
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HUMECTANTS (DELIVERY SOLVENTS) E-cigarettes use humectants as solvent carriers in e-liquids to produce aerosols that simulate combustible tobacco cigarette smoke.
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Both compounds might pyrolyze, leading to the formation of carbonyl compounds (aldehydes) , which contribute to potential health risks in e-cigarette users (for discussion about carbonyl compounds, see the subsequent section in this chapter)
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From page 158... ...
They identified numerous case reports and several small studies that identified a "toxidrome" for PG toxicity that can result following repeated, relatively high-dose intravenous administration of PG. The adverse effects include hyperosmolarity, lactic acidosis, hemolysis, central nervous system (CNS)
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From page 159... ...
conducted a relatively detailed pharmacokinetic analysis of PG following intravenous administration of PG at different dose rates, administered over 4 hours. The elimination half-life of PG was dose dependent; at doses of either 3 or 4.5 g/m2 (over 4 hours)
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From page 160... ...
TABLE 5-2 Plasma Pharmacokinetics of Propylene Glycol Given as a 4-Hour Intravenous Infusion 160 Maximum Plasma Cl (ml/ AUC (µg × Patient Dose MTQ Dose PG Dose PG Concentration t1/2 minute/ hour/ml/ Initials (mg/m2)
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From page 161... ...
No studies have evaluated blood concentrations of PG in subjects using e-cigarettes or other vaping devices with PG as the humectant. Evidence of Health Effects from Occupational Exposures to PG There is relatively limited evidence of toxicity from occupational exposures to PG.
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From page 162... ...
Relevance of Occupational Exposures and Clinical Case Reports of Pharmaceutical Exposures of PG to Exposures from E-Cigarettes Although the clinical case reports of PG exposures demonstrate that high-dose oral and intravenous exposure to PG can induce toxicity, the relevance of those studies to potential health effects of PG from e-cigarettes depends on the dose and pharmacokinetics of PG following inhalation exposure through e-cigarettes. Burstyn (2014)
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. There are no studies of clinical measures of potential PG toxicity (e.g., anion gap, lactic acidosis)
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Of more relevance are animal studies using inhalation exposures to PG. Konradova and colleagues (1978)
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Bioassays on PG for Assessment of Organ System Function Because of the well-documented nephrotoxic effects of ethylene glycol, early studies on the toxicity of PG focused on potential effects of chronic PG exposure on kidney functions. Van Winkle and Newman (1941)
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From page 166... ...
The authors define a shisha-pen as "an electronic cigarette (e-cigarette) variant that is advertised to mimic the taste of a water pipe, or shisha.
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. A study of 10 male and 4 female volunteers who were administered glycerol in orange juice with each meal at a dose of 1.3 to 2.2 g/kg/day for 50 days reported no evidence of toxicity or adverse effects on blood or urine production.
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. Most of the dose of orally administered glycerol is metabolized in about 2.5 hours, with 7 to 14 percent of eliminated glycerol unchanged in urine.
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. Repeated dose toxicity studies Because glycerol has been used extensively as a vehicle for drug delivery in many drug toxicology studies, Gad and colleagues (2006)
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. They determined a lowest observed adverse effect level for local irritant effects on the upper respiratory tract of 1,000 mg/m3.
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measured the mutagenicity of mainstream tobacco smoke condensate in the presence and absence of various concentrations of glycerol (5, 10, and 15 percent) and found no difference in mutagenicity in the presence or absence of glycerol.
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Conversely, altogether 15 samples produced by three other manufacturers tested negative. Most e-cigarette liquids do not contain ethylene glycol and, where present, it is at levels that are not likely to contribute significantly to adverse health effects.
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. Similar to combustible tobacco cigarettes, concentrations of menthol in this study varied from 3,700 to 12,000 μg/g.
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substitution of e-cigarettes for their usual combustible tobacco cigarettes.
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Although few studies have examined the effects of flavoring substances administered by inhalation, there are some chemicals that, although approved for ingestion, have established adverse health effects when inhaled. Table 5-4 presents an overview of common flavorings and their inhalation toxicity.
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176 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 5-4 Overview of Common Flavorings and Their Inhalation Toxicity Chemical Group Flavoring Chemical CAS Number Flavor Type Nature Identical Alcohols Geraniol 106-24-1 Floral Menthol 2216-51-5 Mentholic Thymol 89-83-8 Herbal Eugenol 97-53-0 Spicy Acids Butyric acid 107-92-6 Cheesy Valeric acid 109-52-4 Cheesy 2-Methylbutyric acid 116-53-0 Acidic Esters Ethyl butyrate 105-54-4 Fruity 2-Methylbutyrate 105-37-3 Fruity Methyl cinnamate 103-26-4 Balsamic Methyl salicylate 119-36-8 Minty Lactones g-nonalactone 104-61-0 Coconut d-decalactone 705-86-2 Coconut Aldehydes Geranial 141-27-5 Citrus Benzaldehyde 100-52-7 Fruity Cinnamaldehyde 104-55-2 Spicy Vanilin 121-33-5 Vanilla
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TOXICOLOGY OF E-CIGARETTE CONSTITUENTS 177 Respiratory Flavor Descriptor Irritant Inhalation Toxicity Sweet, floral, fruity, rose, waxy, citrus Peppermint, cooling, mentholic, minty Herbal, thyme, phenolic, medicinal camphor Sweet, spicy, clove, woody Sharp, dairy-like, cheesy, buttery, with Mouse LC > 500 mg/m3 a fruity nuance Acidic and sharp, cheesy, sour milky, Mouse LC50 > 4,100 tobacco, with fruity nuances mg/m3/2 hours Acidic, fruity, dirty, cheesy with a fermented nuance Fruity, juicy fruit, pineapple, cognac Sweet, ethereal, rummy, grape, winey Sweet, balsam, strawberry, cherry, cinnamon Wintergreen, mint Coconut, creamy, waxy, sweet, buttery, oily Coconut, creamy, fatty, buttery, milky, and nutty with a slightly fruity nuance Citrus, lemon Almond, fruity, powdery, nutty, and Mouse LC > 500 mg/m3 benzaldehyde-like Rat LC > 500 mg/m3 Sweet, spice, cinnamon red hots, warm Sweet, vanilla, creamy, chocolate Mouse LC > 41,700 µg/ kg/2 hours Rat LC > 41,700 µg/ kg/4 hours continued
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From page 178... ...
178 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 5-4 Continued Chemical Group Flavoring Chemical CAS Number Flavor Type Ketones Diacetyl 431-03-8 Buttery Acetyl propionyl 600-14-6 Buttery Raspberry ketone 5471-51-2 Fruity Heterocycles Oxygen Furfural 98-01-1 Bready containing 5-Methylfurfural 620-02-0 Caramellic Maltol 118-71-8 Caramellic Nitrogen 2-Acetylpyrazine 22047-25-2 Popcorn containing 2,3,5-Trimethylpyrazine 14667-55-1 Nutty 2-Acetylpyrrole 1072-83-9 Musty Sulfur 2-Isopropyl-4-methylthiazole 15679-13-7 Fruity containing 2-Isobuthylthiazole 18640-74-9 Green Sulfur Compounds Mercaptans Furfuryl mercaptan 98-02-2 Coffee Thiomenthone 38462-22-5 Sulfurous p-Menthene-8-thiol 71159-90-5 Citrus
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TOXICOLOGY OF E-CIGARETTE CONSTITUENTS 179 Respiratory Flavor Descriptor Irritant Inhalation Toxicity Sweet, creamy, buttery, pungent, with a pungent caramellic nuance Buttery, nutty, toasted, caramellic, diacetyl and acetoin notes Sweet, berry jam, raspberry, ripe, floral Brown, sweet, woody, bready, nutty, Human TCLO 310 µg/ caramellic with a burnt astringent m3 nuance Rat LC50 175 ppm/6 hours Sweet, caramellic, bready, brown, coffee-like Sweet, caramel, cotton candy, jam, fruity, baked bread Musty, roasted, corn chip, popcorn, nutty, potato-like Nutty, musty, powdery cocoa, potato, musty Musty, nutty-like with a coumarin nuance Musty alliaceous, earthy sulfury, slight fruity, coffee, meaty Green, vegetable, tomato-like with raw musty nuances Roasted coffee, sulfurous, with a burnt match note Fruity, berry, and tropical with a raspberry, minty nuance Grapefruit, fresh, tropical, juicy, mango continued
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From page 180... ...
The study used the gas chromatography–mass spectrometry method and found that 20 of the 39 refill fluids contained cinnamaldehyde at concentrations that were cytotoxic to human embryonic and lung cells in the cell viability assay. The study also revealed that aerosol generated from a single product (cinnamon Ceylon)
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From page 181... ...
The benzaldehyde doses inhaled using 30 puffs from flavored e-cigarettes were often higher than doses inhaled from a combustible tobacco cigarette. The estimated median daily inhaled dose of benzaldehyde from cherry-flavored e-cigarettes was 70.3 μg, a level of exposure more than 1,000 times lower than the permissible exposure limit (PEL)
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From page 182... ...
The amount of carbonyl compounds in e-cigarettes varied significantly not only among different brands but also among different samples of the same products. Although, in most cases, detected levels of carbonyl compounds were lower than those in combustible tobacco cigarette smoke, very high levels of formaldehyde were also reported in e-cigarette aerosols (a comparison of toxicants from combustible tobacco cigarette smoke and e-cigarette aerosols is discussed in Chapter 18)
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From page 183... ...
at levels 86 to 544 times lower than combustible tobacco cigarette smoke. Table 5-5 summarizes experimental studies to determine carbonyl compounds in e-cigarette aerosols, their setups (i.e., methods to trap and analyze carbonyls, e-liquids used)
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. Heating direct trapping on element with 1.6-Ω DNPH-sorbent, HPLC resistance, 2,200-mAh battery Tayyarah and Long, Machine smoking Two disposable and (1)
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From page 185... ...
, direct Propionaldehyde: 40–1,500 trapping on cartridges ng/puff (hydroquinone and DNPH) , HPLC Goniewicz et al., 2014 Machine smoking 11 popular Polish No detailed Formaldehyde: 21–374 ng/puff (puff volume: 70 ml, brands; no detailed information Acetaldehyde: 13–91 ng/puff puff duration: 1.8 information on available Acrolein: 4.6–201 ng/puff seconds, puff interval: e-cigarette properties (at 20 W)
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From page 186... ...
Several studies looked at the potential mechanisms for generating carbonyl compounds in e-cigarettes. In addition to temperature and effects from potential overheating, airflow and catalytic properties of metal heating coils may influence the occurrence of decomposition products.
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From page 187... ...
-dependent, can undergo thermal decomposition to generate reactive aldehydes capable of contributing to oxidative tissue injury, including potential DNA damage. However, for other devices, the levels of aldehyde were very low, relative to both typical indoor air and the levels found in combustible tobacco cigarette smoke.
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From page 188... ...
The battery output voltage significantly affects the concentration of carbonyl compounds in the e-cigarette aerosol, and high-voltage e-cigarettes may expose users to high levels of carbonyl compounds. Formaldehyde also reacts with PG and glycerol during aerosolization to produce hemiacetals.
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From page 189... ...
evaluated the effect of e-cigarette heating coil temperature on formaldehyde formation. Using an infrared camera to measure the maximum heat coil temperature and Fourier-transform infrared spectrometer to measure gas-phase formaldehyde, the authors found that, in some of the commercial e-cigarettes tested, the levels of formaldehyde were greater than those detected in combustible tobacco cigarettes, and as high as 14.1 μg/puff.
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From page 190... ...
They also found that the production of aldehydes was exponentially dependent on concentration of flavoring compounds. Sucrose, a sweetener and flavor enhancer detected in e-liquids in concentrations from 0.76 to 72.93 μg/g, also has been suggested as a potential ingredient that may thermally degrade to produce carbonyl compounds (Kubica et al., 2014)
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This dose is much higher than the estimated daily dose of formaldehyde from combustible tobacco cigarettes, which is approximately 3 mg/pack of 20 combustible tobacco cigarettes (150 μg/cigarette)
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These variations could be due to use of purer nicotine extract or minimization of nicotine oxidation. These minor tobacco alkaloid concentrations in e-liquids are much lower when compared with combustible tobacco cigarettes, which have minor tobacco alkaloid concentrations in the range of 659–986 μg/g for nornicotine, 8.6–17.3 μg/g for myosmine, 127–185 μg/g for anabasine, 927–1,390 μg/g for anatabine and 23.4–45.5 μg/g for isonicoteine (comparisons between e-cigarettes and
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. Nicotine-related impurities are less toxic than nicotine, but the health effects of these minor tobacco alkaloids to e-cigarette users, especially at high levels, is unknown.
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. Oxidants are also derived from a device's lithium ion battery, similar to that used in combustible tobacco cigarette filters and e-cigarette cartomizers (Lerner et al., 2015a)
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In their mouse model, these free radicals caused oxidative stress and airway inflammation and disrupted antibacterial and antiviral responses. Lerner and colleagues (2015b)
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All of the products tested contained some potentially toxic compounds. The authors detected diethylene glycol, ethylene glycol, and ethanol at levels within limits permitted for food and pharmaceutical products.
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Pharmaceutical Drugs In addition to the toxicants described above, although rare, e-cigarette users may also be exposed to pharmacological components in their devices' e-liquids. For example, one study found evidence of a weightloss medication (rimonabant)
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Conclusion 5-3. There is substantial evidence that except for nicotine, under typical conditions of use, exposure to potentially toxic substances from e-cigarettes is significantly lower compared with combustible tobacco cigarettes.
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The thick, copper-silver wire was also attached to the air tube and mouthpiece at tin solder joints. The same study group detected 35 of 36 selected elements in electronic hookahs and disposable e-cigarettes; in comparison, the authors found 15 of these elements in combustible tobacco cigarette smoke (Williams et al., 2017)
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From page 200... ...
. While many of the studies on e-cigarettes and metals have been done with first- or second-generation devices, a recent study has compared metal concentrations in e-liquid before being in contact with the device to metal concentrations in the aerosol generated after heating the coil of 56 modified e-cigarette devices from daily e-cigarette users (Olmedo et al., 2018)
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. So far, only one published study has compared metal concentrations in e-cigarette emissions to metal biomarker concentrations in an
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From page 203... ...
is an established carcinogen. Few studies have measured the toxic characteristics of metals in e-cigarette aerosols, although in principle, metal toxicity would not necessarily change compared with metal exposure from other sources.
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Cadmium, which is a metal typically found in e-cigarettes, is found at a markedly lower level than in combustible tobacco cigarettes. However, the number of metals appears to be large, even larger than for combustible tobacco cigarettes.
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There is limited evidence that the number of metals in e-cigarette aerosol could be greater than the number of metals in com bustible tobacco cigarettes, except for cadmium, which is markedly lower in e-cigarettes compared with combustible tobacco cigarettes. REFERENCES Aberer, W., T
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2014. Carbonyl compounds generated from electronic cigarettes.
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2013. Analysis of refill liquids for electronic cigarettes.
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2014. Electronic cigarettes: Overview of chemical composition and exposure estimation.
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2014. Chemical hazards present in liquids and vapors of electronic cigarettes.
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2014. Carbonyl compounds in electronic cigarette vapors: Effects of nicotine solvent and bat tery output voltage.
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2017. Determination of volatile organic compounds including alcohols in refill fluids and cartridges of electronic cigarettes by headspace solid-phase micro extraction and gas chromatography–mass spectrometry.
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2011. Determination of carbonyl compounds generated from the electronic cigarette using coupled silica cartridges impregnated with hydroquinone and 2,4-dinitrophenylhydrazine.
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2016. Detec tion of 5-hydroxymethylfurfural and furfural in the aerosol of electronic cigarettes.
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2015. Toxicity assessment of refill liquids for electronic cigarettes.
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2017. Elements including metals in the atomizer and aerosol of disposable electronic cigarettes and electronic hookahs.
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